K16F/E22F Mutation Promotes Oligomerization and Alters β-Sheet Topology of Aβ16–22 Peptides: Insights from Molecular Dynamics Simulations

Amyloid-β (Aβ) aggregation into toxic oligomers and fibrils is a hallmark of Alzheimer's disease. The Aβ₁₆₋₂₂ fragment plays a critical role in the early stages of the aggregation of full-length Aβ peptides. Aggregation of Aβ₁₆₋₂₂ is primarily driven by hydrophobic interactions within the LVFF core and electrostatic attraction between flanking residues K16 (+) and E22 (-). To dissect the relative contributions of these forces, we introduced a K16F/E22F double mutation, which eliminates charged residues while enhancing hydrophobicity and aromaticity. This substitution provides a controlled system to evaluate how specific interactions influence aggregation behavior. Using a novel computational protocol, featuring a strategically designed 4-mer system, multiple independent and long-time scale trajectories, and specialized analysis, we directly tracked and comprehensively characterized the oligomerization process. The mutation significantly enhanced both intra- and intermolecular interactions, promoting aggregation. It also altered the oligomerization pathways, as reflected in the distinct distribution across ten possible states formed by four Aβ₁₆₋₂₂ peptides. Furthermore, while the wild-type peptide predominantly formed antiparallel β-sheets, the mutant favored parallel and mixed β-sheet arrangements. These results indicated that increased hydrophobicity and aromaticity facilitate more stable and polymorphic aggregation pathways. Our findings highlight the dominant role of hydrophobic interactions in early-stage Aβ aggregation and emphasize the therapeutic potential of targeting hydrophobic hotspots, such as the LVFF core, while accounting for structural polymorphism rather than focusing solely on disrupting electrostatic interactions.